KR940001776B1 - Imidazol phenyl derivatives - Google Patents

Abstract

New title compounds of formula (I) are prepared by reacting N-cyano-N'-[4-(imidazol-4-yl)phenyl amidine with 2-(4-methoxy phenyl) ethylamine in the presence of methanol or the mixture solvent of H2O and methanol. Pref. the compound (I) is N-[2-(4-methoxyphenylethyl) -N'-[4-(imidazol- 4-yl)phenyl formamidine. In the formula (I), R1=H, C1-3 lower alkyl or phenyl. (I) are useful as an antiulcer drug acting on histamine H2 receptor.

Description

N-methoxyphenylethyl-N'-imidazolylphenylamidine derivatives and preparation method thereof

1 is a graph of gastric secretion inhibition rate according to the dosage,

Figure 2 is a graph of acidity lowering effect with dose.

The present invention relates to a novel N-methoxyphenylethyl-N'-imidazolylphenyl amidine derivative having an antiulcer action as a compound represented by the following general formula (I) and a method for producing the same.

Wherein R is hydrogen or methyl group and R ₁ is hydrogen, lower alkyl group of C _1-3 or phenyl group.

Representative compounds of the present invention are novel compounds having a phenylformamidine structure as the parent nucleus, and belong to the H ₂ -receptor antagonist, which have excellent anti-ulcer effect, less side effects, and appropriate action time.

As a substance having a structure similar to the compound of the present invention known to date, a substituted imidazolyl phenyl amidine derivative having the following structural formula described in Korean Patent Publication No. 88-1317 is already known.

Wherein R, R ₁ and R ₃ are the same or different and are a hydrogen atom or a lower alkyl group, and R ₂ is a straight or branched alkyl, alkenyl or alkynyl group, cyano group, hydroxyl group, substituted or Substituted or unsubstituted, which may further contain unsubstituted cycloalkyl or substituted alkyl, bicyclic, aralkyl or aryl groups (optionally substituted by halogen, methyl, methoxy or methylenedioxy groups) or hetero atoms Ring heterocyclealkyl or heterocyclegroup).

In the above-mentioned patents, in the specification, aralkyl is limited to benzyl group and aryl group is limited to phenyl group, and thus imidazolylphenylamidine derivatives substituted with monomethoxybenzyl or monomethoxyphenyl are known. The compound described in patent application No. 90-10522, which has been filed by the applicant of the present invention as a domestic patent, is an imidazolylphenyl amidine derivative substituted with dimethoxyphenyl, and thus has a structure different from that of the target compound of the present invention. Are different and the compounds of the present invention have more superior pharmacological effects than the compounds described in these citations.

In the present invention, "lower alkyl group of C _1-3 " means a methyl, ethyl or propyl group.

The compounds of the present invention can be administered orally or parenterally, with oral administration being more preferred. The compounds of the present invention can be administered as free bases or pharmaceutically acceptable salts thereof, which are administered as a medical or pharmaceutical composition with carriers or diluents which can be used in the manufacture of a medicament. Acceptable salts include organic acid salts such as hydrochloride, malate or fumarate.

The pharmaceutical composition of the present invention is preferably administered in a capsule or tablet form, but may be formulated and administered as a conventional pharmaceutically acceptable preparation such as a continuously released preparation, a sugar preparation, a test preparation or an injection.

The daily allowable dose is 1 mg to 2000 mg, preferably 3 mg to 200 mg.

Particularly preferred compounds among the compounds represented by general formula (I) according to the present invention are N- [2- (4-methoxyphenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] form Amidine and its hydrochloride form.

The gastric secretion inhibitory effect and the acid excretion effect of the compound according to the present invention were tested and the test method and results are as follows.

1) The inhibition rate on the gastric secretion:

* Experimental Animals: Spraque-Dowly male rats were purchased at the Tertiary Experimental Animal Research Center and used for the experiment, which weighed 170-220 g after preliminary breeding for about 1 week.

* Experimental Method: The rats are fasted for 24 hours (water is freely supplied), and then anesthetized with ether to perform laparotomy. Take out the stomach and ligation the pyloric part to the duodenum from the stomach with sutures and then administer the drug into the duodenum. The drug should be dissolved in distilled water in principle, otherwise it was used after suspension. After 6 hours of ligation of the pyloric region, the stomach was removed, gastric juice was collected, centrifuged at 3,500 rpm for 10 minutes, the number of ml was measured, and the amount of gastric volume per 100 g of body weight was corrected to correct individual differences due to body weight. It was calculated (Table 1).

Table 1. Gastric juice amount (ml / 100g)

Note> a): Mean ± standard error (S.E.)

*: P <0.01, significant difference with control.

2) Acid output action (Acid output):

* Method is same as 1), take 2ml of collected gastric juice and titrate to pH 7.0 with 0.02N-NaOH

The acidity per hour per 100 g of body weight (Table 2).

Table 2. Acid emissions per hour (titrated with 0.02N-NaOH)

Note> *: P <0.01, significant difference with control.

For reference, with respect to the experimental results of Table 1 and Table 2, the graph of gastric secretion inhibition rate according to the dosage is shown in FIG. 1, and the graph of the acidity lowering effect according to the dosage is shown in FIG.

3) Acute Toxicity Test

* Experimental Method: After pre-breeding ICR-based females and male mice with a weight of 20-25g in the nursery, 10 females of 5 males and 5 males each were fasted for 3 to 4 hours before the experiment, followed by oral administration of the drug. . Compound (1) of Example 1 of the present invention is poorly soluble in water, suspended in 1% CMC, orally administered by dose, and freely supplied with feed and water for 2 weeks to check general condition. LD 50 was taken as the dose at which half the animals die and was calculated by the Litchfield Wilcoxon method.

Results: LD 50 of Compound (1) of Example 1 of the present invention was 5610 mg / kg. (Compound (1) LD 50 = 5610 mg / kg mouse, oral).

N-methoxyphenylethyl-N'-imidazolyl phenyl amidine derivative of this invention represented by general formula (I) is manufactured by the following method.

Wherein R and R ₁ are as defined above.

That is, after the N-cyano-N '-[4- (imidazol-4-yl) phenyl] imidine derivative of the general formula (III) is suspended in alcohol or a mixed solvent of water and alcohol, an equimolar amount of general 2- (4-methoxyphenyl) ethylamine of formula (II) is added and stirring is continued at room temperature until the amidine crystal is dissolved. After completion of the reaction, the resulting solution was concentrated under reduced pressure to remove the solvent, the oily residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain the target compound of formula (I). .

Subsequently, the obtained crystals are dissolved in anhydrous methanol or acetone, and then passed through hydrogen chloride gas to obtain the hydrochloride salt of formula (I).

Example 1

Process for the preparation of N- [2- (4-methoxyphenyl) ethyl] -N '[4- (imidazol-4-yl) -phenyl] formamidine.

4.22 grams (0.02 mol) of N-cyano-N '-[4- (imidazol-4-yl) phenyl] formamidine are suspended in 100 milliliters of methanol. 3.33 grams (0.02 mol) of 2- (4-methoxyphenyl) ethylamine was added dropwise at room temperature, followed by continued stirring at room temperature until the amidine crystals dissolved. After completion of the reaction, the resulting solution was concentrated under reduced pressure, and then the residue on oil was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.1 g of the title compound.

* Yield: 80%

* Appearance and melting point: White crystal, 158 ° ~ 160 ℃

* 1 H NMR (DMSO-d ₆ ) δ 2.8 (2H, t, -CH ₂ ), δ 3.5 (2H, t, -CH ₂ ), δ 3.75 (3H, S, -OCH ₃ ), δ 7.12 (1H, S, -NCH =), δ 7.58, 6.9 (8H, m, arom), 7.7, 7.3 (2H, S, imidazole-H).

Example 2

Process for preparing N- [2- (4-methoxyphenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] formamidine hydrochloride.

The crystals obtained according to Example 1 are dissolved in anhydrous methanol or acetone and then passed through hydrogen chloride gas in a cooled state to obtain the hydrochloride salt of the title compound.

* Yield: 92%

* Appearance and melting point: White crystal, 226 ° ~ 230 ℃

Claims (6)

Compound of formula (I) and salts thereof Wherein R is hydrogen or methyl group and R ₁ is hydrogen, lower alkyl group of C _1-3 or phenyl group. A compound according to claim 1, wherein the compound of general formula (I) is N- [2- (4-methoxyphenyl) ethyl] -N '-[4- (imidazol-4-yl) phenyl] formamidine And salts thereof. The compound according to claim 1 or 2, wherein the hydrochloride compound of formula (I) is a compound selected from hydrochloride, malate or fumarate. N-cyano-N '-[4- (imidazol-4-yl) phenyl] amidine derivative of formula (III) and 2- (4-methoxyphenyl) ethylamine of formula (II) Or reacting at room temperature in the presence of a mixed solvent of water and alcohol to prepare a compound of formula (I) and salts thereof. Wherein R is hydrogen or a methyl group and R ₁ is a lower alkyl group or a phenyl group of hydrogen C _1-3 . The method according to claim 4, wherein the compound of formula (III) and the compound of formula (II) are reacted in equimolar amounts. The method of claim 4, wherein the alcohol is methanol.